Insect-cell-based flu vaccine looks good in clinical trial

Apr 12, 2007 (CIDRAP News) – An influenza vaccine grown in insect cells instead of chicken eggs proved safe and yielded a good immune response in a trial in healthy adults, possibly signaling a significant advance in flu vaccine production technology, according to a report published this week in the Journal of the American Medical Association (JAMA).

The vaccine also reduced the incidence of actual flu by 86% in comparison with a placebo group, though the groups were too small to make this finding statistically significant, according to the report by John Treanor, MD, of the University of Rochester, and colleagues.

The vaccine, made by Protein Sciences Corp., Meriden, Conn., has hemagglutinin, the protein found on the surface of flu viruses, as its sole active ingredient, or antigen. The protein is produced by infecting insect cells with a harmless virus that has been altered to contain the gene for hemagglutinin. Most conventional flu vaccines consist of whole, killed flu viruses or viral fragments that contain several proteins, not just hemagglutinin (though one vaccine uses a live, weakened virus).

Cell-culture technology makes it possible to develop and produce flu vaccines faster than with the traditional egg-based method, which takes about 6 months. It also is considered safer, because there is no production of live flu viruses, and, in the case of the Protein Sciences vaccine, no preservatives or adjuvants are used.

Protein Sciences expects to obtain Food and Drug Administration (FDA) approval of its vaccine, called FluBlok, in time for the 2008-09 flu season, according to Manon M.J. Cox, the company's chief operating officer and the senior author of the JAMA report.

The FDA has granted the vaccine "fast track" status, and Protein Sciences plans to begin submitting its application documents in the fourth quarter of this year, Cox told CIDRAP News by e-mail.

No cell-based flu vaccine has yet been approved in the United States. The European Union licensed a cell-based flu vaccine made by Solvay Pharmaceuticals several years ago, but the company has not sold any of it, according to Cox.

The virus used to make the Protein Sciences vaccine is a baculovirus, a type that infects a few insect species and is commonly found on green vegetables but does not grow in mammalian cells, according to a recent journal article by Cox and D. Karl Anderson, also of Protein Sciences. A serving of coleslaw typically contains millions of baculovirus particles, the article says.

The vaccine is made by cloning hemagglutinin genes from target flu viruses and splicing them into baculoviruses. The recombinant baculoviruses are then used to infect lab-grown cells derived from the fall armyworm (Spodoptera frugiperda), according to Cox and Anderson. The viruses grow in the cells, producing hemagglutinin.

The FluBlok study was sponsored by Protein Sciences and conducted during the 2004-05 flu season. The vaccine contained hemagglutinin from the same three strains as were used in conventional flu vaccines that season: a New Caledonia strain of influenza A/H1N1, a Wyoming strain of influenza A/H3N2, and a Jiangsu strain of influenza B.

The investigators used 460 volunteers, randomly divided into three groups. One group received a placebo; the other two groups received one of two vaccine formations. One formulation contained 45 micrograms (mcg) of hemagglutinin from the H3N2 strain and 15 mcg each of the H1N1 and B hemagglutinins, for a total of 75 mcg; the other contained 45 mcg of hemagglutinin from each of the three flu strains, for a total of 135 mcg.

The immunogenicity criterion used in the study was a fourfold or greater increase in serum hemagglutination-inhibition antibody at 28 days after vaccination. For the H1N1 strain, this response occurred in 3% of the placebo group, 51% of the 75-mcg vaccine group, and 67% of the 135-mcg group. Responses to the H3N2 strain were found in 11% of the placebo group, 81% of the 75-mcg group, and 77% of the 135-mcg group. For influenza B, an immune response was seen in 4% of the placebo group, 65% of the 75-mcg group, and 92% of the 135-mcg group.

Thirteen cases of laboratory-confirmed flu infection occurred among the volunteers, but only nine met the CDC case definition for flu (fever plus sore throat or cough). These nine cases involved 7 of the 153 placebo subjects (4.6%), 2 of 150 volunteers in the 75-mcg vaccine group (1.4%), and 0 of 151 volunteers in the 135-mcg group. The four lab-confirmed cases that didn't meet the CDC case definition included one in the placebo group, two in the 75-mcg group, and one in the 135-mcg group.

"When considering both vaccine groups combined, the cumulative incidence of culture positive CDC-defined influenza-like illness was reduced by 86%," the report states. The authors describe this as "preliminary" evidence of protection against flu, because the sample size was small.

As for safety, rates of local and systemic side effects of the vaccine were low. Injection-site pain was more common in the vaccine recipients than the placebo group, but it was mild in 97% of cases. The rates of systemic symptoms were similar in the vaccine and placebo recipients, and there were no reports of fever.

The responses to the 75-mcg vaccine met the European Union criterion for flu vaccine licensure, but the 135-mcg formulation triggered a stronger response "and might be expected to provide greater or longer-lasting protection," the authors write. They add that the 135-mcg formulation should be used in further development of the vaccine and that "these doses are well within the production capacity of the system."

Of the lab-confirmed flu infections, three were influenza B and 10 were H3N2. All 10 of the latter were found to be A/California/7/2004-like viruses, a variant that was not included in the 2004-05 vaccine and that accounted for 75% of the H3N2 isolates in the United States in 2004-05.

The report says others have suggested that neuraminidase, another flu virus protein that is typically found in conventional flu vaccines but not in FluBlok, may be important for protection when the hemagglutinin in the vaccine does not closely match the circulating virus. The current findings, however, suggest that "it is possible to generate a substantial amount of protection in an immunologically primed population against influenza with a pure hemagglutinin vaccine, even in the presence of significant antigenic drift."

Treanor, commenting by e-mail, said, "It's unclear what our observation really means about this, but the protection we saw against the drifted virus (86%) was comparable to that seen with the inactivated vaccine in another study (77%). I would not want to make too much of this, but it does suggest that a hemagglutinin-only vaccine can provide reasonable protection against a drifted virus."

The authors say the approach used to make FluBlok has already been used to make effective vaccines against hepatitis B virus and human papillomavirus. They add that using recombinant baculovirus is especially appropriate for producing flu vaccine because genes can be copied and inserted into the virus quickly, making it easier to update the vaccine.

"In addition, the extraordinarily high yields of protein possible in this system provide the opportunity to use much higher and potentially more effective doses of vaccine," the report states.

Michael T. Osterholm, PhD, MPH, said the new findings may signal a "breakthrough" in the ability to quickly produce large amounts of flu vaccine, in a world that currently can produce only about 350 million doses of trivalent flu vaccine annually.

"Other cell-based vaccines are using the same viruses we use in egg production. We now have this novel flu vaccine in which we use the baculovirus to serve as the means to produce this recombinant hemagglutinin," said Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, which publishes CIDRAP News.

With this technology, he said, "production could be ramped up much more quickly and from the standpoint of quantity of vaccine this could be a major breakthrough."

Commenting that the vaccine seems to have good efficacy, Osterholm added, "This is not just an incremental increase in our vaccine work; to me this is truly a major and exciting step forward. . . . There's a lot more work to do here, but I think it's very important that it's gotten this far."

Cox said the baculovirus technology makes it possible to move a flu vaccine into full production in about 6 to 8 weeks from the time the target viruses are identified. In response to the original H5N1 avian flu outbreak in Hong Kong in 1997, Protein Sciences created an H5 hemagglutinin vaccine in 8 weeks, according to Cox and Anderson's recent report.

Treanor commented, "I don' t really know how much faster this vaccine is [compared with egg-based vaccines] but I am guessing it might shave a couple of weeks off the production time—that is, a baculovirus vaccine might be ready in mid August compared to early September. This isn't a big difference in time but could mean many thousands more people getting vaccinated."

Cox said she expects that the vaccine will cost about $1 per dose once full-scale production is under way, but the initial cost will be higher.

Protein Sciences launched trials of FluBlok in children and the elderly last October. Cox said both studies will be concluded by the end of May and reports of the results are expected by the end of June.

Treanor JJ, Schiff GM, Hayden FG, et al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine. JAMA 2007 Apr 11;297(14):1577-82 [Abstract]

See also:

Protein Sciences page with information on the vaccine
http://www.flublok.com/

January 2007 report by Cox and Anderson in Influenza and Other Respiratory Viruses
http://www.blackwell-synergy.com/doi/full/10.1111/j.1750-2659.2006.00007.x?cookieSet=1

Jun 27, 2005, CIDRAP News story "Momentum builds for cell-culture flu vaccines"

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